The goal of the proposed research is to elucidate the genetic mechanism controlling the antibody variability and the application of this knowledge to combat inherited and immunodeficiency diseases. Amino acid sequence determination and analyses of inherited antigenic determinants (Gm, Am, Km, Mm and idiotypic markers) will be conducted on immunoglobulins from normal individuals, as well as patients with multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain diseases, hypogammaglobulinemia, idiopathic cryoagglutininemia, cryoglobulinemia and various other immunodeficiency conditions. Results obtained from these studies will be analyzed in order to determine if any correlation exists between the structure of the abnormal immunoglobulins and the diseases with which they are associated. We also are attempting to use the maturation of immunoglobulin producing cells as a simple model system for the investigation of various aspects of differentiation and "regulatory" control of gene expression in other complex genetic systems in higher organisms. BIBLIOGRAPHIC REFERENCES: Johnson, P.M., Faulk, W.P. and Wang, A.C.: Immunological studies of human placentae: subclass and specificity of binding of aggregated IgG by placental endothelial cells. Immunology 31: 659-664, 1976. Wang, A.C. and Wang. I.Y.: Cleavage sites of human IgGl immunoglobulin by papain. Immunochemistry 14: 197-200. 1977.